A recent article published in the journal World Psychiatry reviews the existing evidence for dopaminergic and glutaminergic functioning in individuals considered at “high-risk” for developing “schizophrenia.” The authors found no significant differences between high-risk populations and control groups when analyzing neuroimaging studies from 1960 to 2020, putting the dopamine hypothesis of the cause of “schizophrenia” in question.
“Disruption of dopaminergic and glutamatergic neurotransmission has been proposed to be central to the pathophysiology of schizophrenia. Findings indicate that dopamine and glutamate dysfunction occurs in schizophrenia but raise the question of whether it predates the onset of the disorder. It is possible to investigate neurochemical changes prior to the onset of schizophrenia by studying people at increased risk for developing the disorder,” Robert McCutcheon and co-authors Kate Merritt and Oliver D. Howes write.
Although there has long been criticism of the dopamine hypothesis of “schizophrenia” as the cause of the condition, including a previous meta-analysis that found no support for the hypothesis after analyzing relevant neurochemical processes, the hypothesis continues to maintain prominent status in psychiatry.
Many suggest that it is more accurate to locate the cause of “schizophrenia” in trauma and adverse life events as a counterpoint.
The current study performs a comprehensive statistical meta-analysis of studies from January 1, 1960, to November 26, 2020. The meta-analysis aims to examine whether “greater variability of dopamine and glutamate measures exists in high-risk individuals compared to controls.” In addition, the authors state that comparing high-risk individuals against a control sample will help determine whether dopaminergic and glutaminergic factors precede the onset of “schizophrenia,” which could grant or reduce legitimacy to the causal dopamine hypothesis.
The question is not whether “schizophrenia” involves changes in dopaminergic and glutaminergic functioning, which has been shown to be the case in previous research, but whether these neurochemical processes cause “schizophrenia.”
“In the present paper, we meta-analyzed neuroimaging studies of the dopamine and glutamate systems in individuals at high clinical or genetic risk for psychosis to provide the best estimate of the magnitude and variability of group differences across samples and settings.”
As the quoted passage states, both “clinical risk” and “genetic risk” populations were analyzed in the meta-analysis. Individuals high in clinical risk are defined as:
- schizotypal disorder plus recent-onset functional impairment
- and/or brief intermittent psychotic symptoms
- and/or attenuated psychotic symptoms
While those high in “genetic risk” are defined as:
- non-psychotic relatives of individuals with schizophrenia
- individuals with copy number variants, such as the copy number deletion of 1.5-5 megabases at 22q11.2 – a genetic marker associated with a “~45% lifetime risk of developing psychosis and ~35% lifetime risk of developing schizophrenia.”
Separate meta-analyses were conducted for CHR (clinical high risk) and GHR (genetic high risk) individuals. The average age of the study participant was 26.5 years old, and 52.6% were male.
Studies that included individuals with comorbid substance dependence were excluded because substance use can affect the dopamine system.
5,454 papers were identified in the available research literature for potential inclusion. Only forty-eight of these met the inclusion criteria, which included the above-mentioned risk factors as well as several targets of neuroimaging, such as striatal presynaptic dopamine function, striatal D2/D3 receptor availability, and glutamate or Glx (glutamine-glutamate) concentrations. To be included, the studies needed to analyze these processes for both high-risk individuals and control individuals.
Eight studies of CHR individuals met the inclusion criteria, including 188 CHR individuals and 151 controls. According to the authors, “The two groups did not differ significantly in terms of striatal presynaptic dopaminergic function.” Furthermore, no significant statistical variability between them was found either.
Six studies included individuals at high genetic risk. Four of these examined relatives of individuals with “schizophrenia,” while two reported individuals with the 22q11 deletion syndrome. These included 81 GHR individuals and 105 controls. Again, the authors found no significant difference in striatal presynaptic dopaminergic function between the groups and no significant statistical variability between them.
A similar story emerged for each of the particular neuroimaging targets, from striatal D2/D3 receptor availability to glutamate functioning. The authors did find that Glx (glutamine-glutamate) concentrations were significantly higher in genetic high-risk individuals than in the controls, with a small to moderate effect size (g=0.36). However, they found no such differences in individuals with clinical high risk.
Interestingly, earlier studies included in the meta-analysis were more likely to find significant differences in striatal presynaptic dopaminergic function and D2/D3 receptor availability in individuals at clinical high risk. This was not borne out by the overall meta-analysis, however. In addition, glutamate functioning did not have this variability according to publication date.
The authors conclude:
“Initial studies of striatal presynaptic dopaminergic function in CHR individuals provided evidence of striatal dopaminergic hyperactivity. The lack of a significant difference between CHR subjects and controls in the current meta-analysis is therefore potentially surprising.
Increased thalamic Glx concentrations are found in individuals at increased genetic risk for psychosis. There are no significant differences between high-risk individuals and controls in striatal presynaptic dopaminergic function, striatal D2/D3 receptor availability, prefrontal cortex glutamate or Glx, hippocampal glutamate or Glx, or basal ganglia Glx. There is also no evidence of increased variability of dopamine or glutamate measures in high-risk individuals compared to controls.
Significant heterogeneity, however, exists between studies, which does not allow to rule out an increase in striatal dopamine synthesis and release capacity in subjects at increased clinical risk.”
McCutcheon, R. A., Merritt, K., & Howes, O. D. (2021). Dopamine and glutamate in individuals at high risk for psychosis: A meta-analysis of in vivo imaging findings and their variability compared to controls. World Psychiatry, 20(3), 405-416. (Link)
At least part of this is due to “schizophrenia” not being a single disease entity, so that these studies are attempts to find single “causes” for the existence of a polyglot entity. There should be no surprised all these sub-entities have confused seekers looking for for a single one.
It’s like trying to find the “cause” of abdominal pain. If you try to find one cause, you’ll be completely baffled and decide it is “incurable,” and spend a lot of money on pain relievers and Ex-Lax. There is no reason to believe that “schizophrenia,” itself definable in so many different ways even within the DSM paradigm, is a “thing” that is caused by another “thing.” It is, at best, a syndrome that could have a wide variety of causes and potential solutions. Should be obvious to anyone who understands science, but apparently a hell of a lot of “mental health professionals” aren’t in that group!
The only people that recover from ‘Schizophrenia’ are the people that reject the medical model.
Does this mean people will stop saying that psychiatric medication causes schizophrenia?
If we accept that antipsychotics do cause something disatrous to some peoples brains, that makes them feel symptoms they claim are just like schizophrenia, then presumably it is not actual real schizophrenia in antipsychotically modified people and so the antipsychotics maybe cause something else to peoples brains. Not schizophrenia.
But the question I am pondering here is not that so much, it is this…
If the meds do not cause real schizophrenia, but symptoms of severe mental illness that mimics psychosis of schizophrenia, with hallucinations and voices and delusions, then presumably whatever upsets the brain on a neurochemical level DOES MATTER. So presumably in some people who have such damage from antipsychotics, mucking up their dopamine or whatever, whatever, to the extent of feeling really unwell in their brain, it may NOT be trauma in THOSE rare cases.
And if that is true, then perhaps schizophrenia IS brain related and not trauma related, it is just that the correct brain issue has not been understood properly yet.
I am all for eradicating psychiatric myths and psychiatric bad treatments. I do however feel that my own schizophrenia, I am now talking only from my own lived experience here, is a real schizophrenia that is depedent on my brain. Somehow my brain is involved at a neurochemical, synaptic, hormonal level. Everyones brain does not come out of a factory!
I think my brain, which is not anyone elses brain, is ill actually.
It is ill maybe in the way a person with alcohol dependency with delirium tremens is ill, or a person with post partum baby blues feels ill, or even a person with premenstrual syndrome feels ill. These involve the brain. And although I may not know what causes my schizophrenia, my schizophrenia and nobody elses, it may well one day turn out to be either caused by my brain or influenced in someway in that way, as brain instability due to hormonal shifts that make the brain behave oddly. Nobody knows much about the presumed factory stock average brain, let alone unique individual brains. I feel we should respect the absolute mystery of all brains and leave everyone’s brain alone. There is no spare brain or a plan B brain or a brain transplant that you can opt for if medication or invasive bad treatment fouls things up. For that reason all experimenting on brains should stop.
The brain is as delicate as a bomb. Tamper with it and the wreckage cannot be repaired. Being as it is a bomb, everyone’s brain should be left to be healed by more holistic ways. That is my view. However I am not the owner of anyone else and so each person should be free to choose what treatment they believe sustains them. I totally disagree with medicating children whose brains are not even developed into delicate bombs yet. They dont even get the chance to evolve that far.
I am against bad treatment. I am against treating the brain. But I do not buy the idea that there is no such thing as a medication or non medication source of brain damage or brain disaster or brain disfunction, one that can bring on symptoms a bit like schizophrenia. If the disrupted antipsychotic awash brain can cause those symptoms then I do not feel it is implausible that the brain does have a bearing in schizophrenia. I have not found what aspect of my brain’s biology causes my schizophrenia, but perhaps it is just because science or some other mode of turning up gnosis, has not been searching for the subtleties. This is not a big deal. We have not discovered the answers to many other scientific enigmas.
Being rude to someone who is experiencing actual brain disruption from where ever it may be emanating from, is like being rude to people who have brain disruption from antipsychotics that make them feel schizophrenic. It is intrinscally unhelpful to disregard one cohort of people who are suffering from hallucinations, voices and delusions, and only lionizing the other cohort.
BOTH need heard.
The reason BOTH cohorts are in my humble opinion not being treating equally is because the group who got given symptoms of what is comparable to schizophrenia, maybe from dopamine chaos caused by antipsychotics, want to move away from that which they think has caused their illness, such as the brain, as in tampering with the brain, so they want to get as far away from the brain as possible, to the extent of never even wanting to mention that “b” word. And because they feel lumbered with a sort of similar to schizophrenia thing that they did not ask for, they want to get far away from the schizophrenia word too. But some people with real schizophrenia that was not their fault either and was categorically not caused by trauma and was not caused by antipsychotics, people who genuinely feel ill, and ill in their brain, a place that keeps giving them the same type of hallucinations, voices and delusions, that those brain damaged by antipsychotics experience, are real people with real schizophrenia who ALSO need help.
In a world of scant resources where EVERYONE needs help, everyone is diverging into antagonistic splinter groups and schisms.
I forsee a future where NOBODY will get the care they need.
With everyone disrespecting anyone in a different faction, with apparently opposing opinions, increasing fragmentation of a once unified protest will occur, and by each group delegitimating other groups who have different, not competing, needs, the overarching “powers that be” will also join in delegitimizing each group, since the process of downplaying any illness will be in full swing, demolishing the lived experience of many different groups will be a form of self sabotage from within that once unified whole. And so one by one those groups will be pushed aside without those overarching “powers that be” even having to bother ever again lifting a lethargic health care finger to the money purse. The groups all getting lost in infighting over finicky word choices will dismantle the potency of the protest from within. Such that the groups will wind up mothballing their own claim to necessary funding.
Those “powers that be” can just say…
Schizophrenia doesnt exist.
Bipolar disorder doesnt exist.
Post partum blues dont exist.
Work related stress doesnt exit.
Eating disorders dont exist.
Alcoholic addiction doesnt exist.
Drug addiction doesnt exist.
Major depression doesnt exist.
etc etc etc.
Oh, but that doesnt matter. The community will exist. But I dont yet see the community coming to change my neighbour’s shitty diapers inbetween listening to a few new bands or eating ice creams at the beach. Where I reside, I heard a statistic that a whole soccer stadium can be filled with people with Altzheimers. Probably that many could be schizophrenia sufferers. Or how about filling the stadium with people whose brains have been disrupted chemically by antipsychotics and who are living in the same abject misery as people with similar hallucinations, voices and delusions as in real schizophrenia?
All I know is the “brain” is frightening to some to discuss because it is like you might be hypnotized into thinking therein lies the problem and nowhere else. Nobody wants to go skipping down the hill of bad choices and bad treatment and bad psychiatry, indeed perhaps for many the idea of any psychiatry at all.
I will not let any psychiatric abuse capture vocabulary in a literal sense, to the point I dare not use words that acknowledge having a brain, or that sometimes it feels disrupted. I am the authority on me. I give myself the freedom to say how I feel, without my liberty to speak causing something like the fetching forth of an injection. I celebrate the complex beautiful mystery that my brain is to me. Any abuse takes away the right I have to own my own body or even refer to it, in any way that, I, as an individual choose. And so as an emancipated individual I take my language back, all the words I wish.
I try to focus only ever on the phenomena of bad treatment. If I ban ever having what I as an individual regards as bad treatment then all words are mine to reclaim or do with what I choose. For words alone fo NOT CAUSE bad treatment. By the time I think my mere words cause bad treatment, I have bought the imposition of bad treatment already. In the same way a badly treated little boy may be taught that mentioning his foot is why he got punished.
It may take him years to reclaim the word foot. His foot. He is allowed to have a foot and not expect bad treatment for having it.
We are all allowed to have a brain without expecting bad treatment.
When someone with schizophrenia says their brain feels ill, they do not do so to illicit bad treatment. They are looking for condolences for enduring a living hell.
Their mention of their hell does NOT deserve or illicit or invite bad treatment.
When an individual person with schizophrenia mentions their brain it does not mean bad treatment to others. Any more than a person mentioning premenstrual syndrome invokes bad treatment to others.
The person with schizophrenia may decide their bogus bad treatment is great for them, and this might solidify a system where bad treatment becomes normalized. I think most people with schizophrenia are not thick. They know bad treatment when they see it. They may be lied to by the purveyors of bad treatment. They may have had little alternative but to buy the lie and hope for the hopeless best. As everyone on the planet did with Prozac. But that does not mean they wanted bad treatment. For them or anyone else.
My own theory is derived from a book called “The Private Life of The Brain”, by Dr Susan Greenfield. She has evidence of discernible differences in the rather aurora borealis hoops of brain waves that do an invisible disco in the brain. These are not chemicals but orchestrations by beautifully synchronized waves, collaboratively responding to external stimuli. She seems to suggest that the waves in people with schizophrenia are similar to those of children. I think what she may mean is the butterfly brain attention span. I suspect that her study may be picking up on control groups who are medicated on antipsychotics. But clearly the waves in all our brains are as important, if not more so, than the crude natural brain neurochemicals. That is why I think the cause of real schizophrenia may be as subtle as a form of light.
(This is garbled but Im doing something else just now. Should be! And so I have not the time or inclination to spellcheck it.)
(And before I go, these are just MY stray responses to this article and its brilliant author. I am not up for arguing, sparring, or feisty debate. Go away if that’s what you want.)
Well, since the “First-generation antipsychotics are dopamine receptor antagonists (DRA) and are known as typical antipsychotics. Second-generation antipsychotics are serotonin-dopamine antagonists and are also known as atypical antipsychotics.”
But since we – at least here at MiA – know all doctors are taught in medical school about anticholinergic toxidrome, which can be created with both the antidepressants and antipsychotics. Which are both anticholinergic drugs, that effect the serotonin and dopamine systems.
It strikes me, as one who suffered her first “psychotic break,” due to the common, adverse, and long run withdrawal effects of an antidepressant being misdiagnosed, and mistreated, initially with a child’s dose of a second generation “atypical antipsychotic.”
That it is likely highly unwise for the ignorant or criminal, big Pharma trusting and money worshipping, psychiatric profession to be messing with the serotonin and dopamine systems of anyone. Especially given the fact that anticholinergic toxidrome and neuroleptic induced deficit syndrome, are both missing from their “invalid” DSM billing code “bible.”
And those two, psychiatric drug induced, syndrome/toxidrome, do indeed create both the positive and negative symptoms of “schizophrenia,” psychiatry’s supposedly “most serious” DSM disorder. And Robert Whitaker did an excellent job in pointing out the iatrogenic etiology of psychiatry’s “bipolar epidemic,” psychiatry’s second most “serious mental illness.”
We certainly don’t need millions of scientific fraud based, medically uninformed, DSM “bible” billing – so called “mental health,” social workers, psychologists, therapists, et al – systemically harming and killing millions of people, out of ignorance. And based upon the psychiatric industries’ “invalid” DSM “bible,” and with their neurotoxic psychiatric drugs.
The drug treatments “suitable” for “Schizophrenia” are classed as Major Tranquillisers. These drugs work through creating a state of indifference.
When a person attempts to withdraw from the Major Tranquillisers they are likely to find themselves reacting to lots of things that didn’t bother them before.
The solution would be for a person to be aware of the problems that need to be looked after but not emotionally invested in them: Equanamity. This is a “no loose state”.
Well, I am not surprised to see all this research went nowhere.
And, because I think a picture is often worth 1000 words, I’m going to post a google image search of the X Files Fox Mulder’s picture of a flying saucer with the words “I want to believe” at the end of this post.
Because it’s actually true that they want to believe and are obsessed with any kind of quick fix that would involve drugs or something that can be monopolized through the patent system. And I will admit that human ingenuity in the past several decades has been remarkable and I am now typing all this on a miraculous invention called The Laptop and I fully understand why, after seeing the human race build such marvelous machines, a whole culture in academia would sprout up that would involve the love of trying to fix human beings the way you could fix a machine.
The mindset and the whole approach to the thinking of it is wrong.
Living creatures did not get put together like a machine. We evolved over a very long period of time, our brains grew, you might say. Evolved certain structures and patterns. This evolution resulted in some structures that maybe somewhat simple, yet actually there was nothing preventing such things as the structure of the brain from evolving in a manner that is so complicated or subtle that we just don’t have the tools to measure the brain this way.
Oh yes, neuroscientists are obsessed with their own tools they use to measure the brain. If all you have is a hammer, everything looks like a nail. I do remember hearing, in a biology course, that in many ways, life very often COULD HAVE — if it had been intelligently designed by a person — been far more simple than it was. Yet, because it evolved rather than was deliberately created, there are structures or systems in us that simply chose to go about certain tasks in the most complicated manner imaginable — stupidly complicated. At least so an engineer would say. “Why do you have to make it so complicated,” anyone would ask the engineer who designed it.
Yet, with life, it doesn’t matter. We evolved that way. All that needs to matter is that it works.
I remember having this same response to scientists who are in a debate over gender and the brain, who are not able to really see all too much in the way of systemic brain differences by gender, at least not with the current measuring tools. (Or, the differences the see are on the small side.) Maybe that all doesn’t matter, that we currently can’t see it with our measuring tools.
Actually, I majored in pure math where, if one does so, it’s possible to understand how certain brain differences that might result in schizophrenia for one person but not another, or that might cause systematic gendered behavior differences or strengths, might still in both cases result in electrical activity which, when measured, looks so similar, we will never be able to figure out the difference unless perhaps some mathematician who was a genius was able to “crack” the code and figure out the pattern difference.
I just wonder, how about if scientists tried to think of Darwin and natural selection, and then ask themselves, what could mental illness be in the brain? Why would it have evolved?
I have written one post about how maybe depression might be something intended to encourage people to live near tall mountains which have guaranteed rainfall even in drought yet are uncomfortable otherwise. The mere fact that women get it more often and men tend to feel compelled, socially, to do what women want and cater to their feelings, even if they seem “irrational” also possibly connected to all that. Women would have forced everyone to move back to the colder mountains after everyone — during a temporary period of lots of brain — moved to a nice warm dry valley. Some women just couldn’t tolerate it. They just didn’t feel right. They wanted to go back to the mountainous areas. The men were annoyed about it but reluctantly agreed. Then the climate got dryer for awhile. People without depression tendencies starved.
As for schizophrenia — that strikes me as tied to paranoia and anxiety and fear. Now I have a tendency towards anxiety but not schizophrenia or psychosis. I also was a victim of the mafia and went through a period where I feared for my life. Oddly enough, after surviving all that, I still have some amount of ptsd and anxiety that I didn’t have before. But, in so many ways, gone are all sorts of inhibitions I used to have. In a way, it was freeing.
It’s interesting, though, how I think maybe my mind just feels a “need” to find something to be a little scared over yet overcome. After the PTSD from the criminal stuff subsided enough, the “fear” needed to go somewhere — so it “transferred” into a fear of heights. I am sometimes afraid of driving over bridges, for instance.
I feel like schizophrenia is related to anxiety somehow. I just wonder, though, maybe the part of our brains originally geared towards hunting in the jungle where, if one steps on something wrong one can fall and really get hurt, or if one is not alert, one can get hurt by an animal, maybe that part of our brains needs exercise and modern day society doesn’t give us enough of that type of mental exercise.
Studies say if you put people in “sensory deprivation” chambers for long enough, e.g., total dark where they are floating on water and seeing and hearing and feeling nothing — they will eventually start to hallucinate. Maybe the boringness of modern day society and excessive amount of security and safety fails to exercise the brains of some who were evolved to be living in a dangerous jungle like environment.
Oh yes, now didn’t the soteria project involve going for walks with schizophrenics and just talking to them? That’s the thing. Schizophrenia or paranoia would tend to force people to not go out in the jungle alone but bring someone with them. I think it’s interesting how they didn’t merely talk to them but they went for walks with them. I bet the walks were very important and sitting down across a table in a sedentary office from someone just isn’t going to be the same.
Here’s the thing. Why can’t academics go and be interdisciplinary about it? Combine all the sciences. Think about human evolution and ask what are the evolutionary origins of mental illness? Speculate the way I am speculating. And then follow through by designing actual studies that would explore such theories, and then see if they have any validity. And then try to use one’s imagination to figure out what sorts of things might help.
Except, this way of thinking is theoretical in the exact same way as Einstein was theoretical about black holes. Had we just limited ourselves to telescopes and never been theoretical in the way Einstein was, we would never have figured out that black holes exist. Because, like how i said maybe parts of the brain are complex beyond our ability to ever be able to “see,” black holes also are incapable of being directly observed.
Oh yes. Another thing. Intuition and what we call “psychic” ability. Some of it may well be something tied to quantum mechanics in the brain — and quantum mechanics IS weird in the sense of sometimes having “retrocausality” with future events in tiny circuitry capable of influencing the past or present somehow. And tiny circuitry is exactly what our brain is full of. And then, go and be Darwinistic about it. If it was theoretically possible for the brain to evolve certain types of intuitive skills that harness quantum mechanics and help one sometimes see into the future in some ways, often with respect to sensing danger, well natural selection does say, if it could have evolved, it would have evolved as it would have given us MAJOR survival advantages.
If that’s what it is, it would be SUPER complex. Then again, nature does not favor or mandate simplicity. Some of those academics who argue that psychic ability is “absurd” have not thought that maybe parts of the brain are mind bogglingly complex. Because there was nothing stopping us from evolving that degree of complexity. It is actually superstitious and un-scientific to argue “it couldn’t possibly be true.”
The scientific thing to do would be to be open minded enough to try to theoretically explore the topic. “How might it be true?” Which most academics won’t do — because they are being paranoid and fear looking “superstitious.” Because academia is a pretty intolerant place full of back stabbing and intimidation, is it not? Culture of intellectual intimidation. Everyone afraid of saying something out of place.
Unfortunately, open-mindedness doesn’t pay nearly so well as authoritarianism and good marketing!
We know that drugs that block Dopamine “switch a person off” and that a person in this state is easily managed. But this doesn’t tell us an awful lot.
I dont know if MIA has seen this article:
(..apologies for being off subject)
Some over the years have said that schizophrenia as been in-aptly named beccause it is not a splitting of the brain as in right/left brain, etc. I guess the correct answer is :maybe… I am no scientist nor do I play one in my postings; so most of this article appears to be me to just “magical words with latinate origin names.” Does that matter? Yes, because it further divides the alleged intelletual scientist from the rest of us. However, in my opinion, this is not science; not any kind of science. And so as this is not science, drugs are made in utter incompetance and lack of any knowledge that in the end damage the brain. Although schizophrenia they say has been around a long time, in my experience, it is in almost all the cases where the alleged symptoms do not show up until after the individual is so drugged. And, since individuals are so drugged, it would be highly unlikely to get any good readings on anyone’s brain. Of course, this does not even include the fact that we are really are to close to the brain to actually study it and know authoritatively about it’s treatment. Treatment in the alleged mental illness field is like throwing darts at blank old board. So real success is so rare that the patient really gets sicker from it or actually gets sick with symptoms they never had before and that’s success…That is success because in the doublespeak world of psychiatry, success is failure and failure is success. Each person has a right to determine their own course of treatment, diagnosis, etc. but I would dare say if you think you have some sort of mental disorder, you must examine the drugs you take or have taken. Of course, some of the drugs you take you may not know—they could be in the soil your food is grown in or the water you drink, etc. Until, we come to terms with our drug culture and the false labeling we do to ourselves and others, we will never be free or know the truth. Thank you.
At least drawing shapes and using sciency sounding words keeps the koolaid drinkable and saleable.
Funny how having an illness makes the sick become second rate citizens in eyes of law, laws that allow all services, starting with psych to harm people.
It is barbaric at best.